Many important drugs are hydrophobic and have limited solubilities in water. In order to attain the expected therapeutic effect of such drug, it is usually required that a solubilized form of the drug be administered to a patient.
For this purpose, there have been developed a number of methods, which are based on the use of: auxiliary solvents; surfactants; soluble forms of the drug, e.g., salts and solvates; chemically modified forms of the drug, e.g., prodrugs; soluble polymer-drug complexes; special drug carriers such as liposomes; and others. Each of the above methods is hampered by one or more particular problems, e.g., the method based on the use of surfactant micelles to solubilize hydrophobic drugs has problems in that most of the surfactants are relatively toxic and that precipitation of hydrophobic drugs occurs when subjected to dilution.
The use of amphiphilic block copolymer micelles has recently been attracting much interest as a potentially effective drug carrier which is capable of solubilizing a hydrophobic drug in an aqueous environment. For example, there have been reported many studies on amphiphilic block copolymer micelles having surfactant-like properties, and particularly noteworthy are the attempts to incorporate hydrophobic drugs into block copolymer micelles stabilized due to the specific nature and properties of the copolymer. For example, EP No. 0 397 307 A2 discloses polymeric micelles of an AB type amphiphilic diblock copolymer which contains poly(ethylene oxide) as the hydrophilic component and poly(amino acids) as the hydrophobic component, wherein therapeutically active agents are chemically bonded to the hydrophobic component of the polymer. Although this polymeric micelle is provided as a means of administering a hydrophobic drug, it is disadvantageous in that it requires the introduction of functional groups into the block copolymer. EP No. 0 583 955 A2, on the other hand, discloses a method for physically incorporating hydrophobic drugs into amphiphilic diblock copolymer micelles described in EP No. 0 397 307 A2. This method, thus, solves the above disadvantage of the chemical bond type polymeric micelle drug. However, the poly(amino acid) segment may induce an immunoreaction and the use of an organic solvent in the preparation of the formulation may pose a problem. Furthermore, because the peptide bonds are cleaved by enzymes in the body, it is difficult to control the release rate of the drug incorporated therein.
EP No. 0 552 802 A2 discloses formation of chemically fixed micelles having poly(ethylene oxide) as the hydrophilic component and poly(lactic acid) as the hydrophobic component which can be crosslinked in an aqueous phase. That is, chemically fixed micelles are prepared by chemically crosslinking the hydrophobic component that constitutes the core, so as to mimic stabilized polymeric micelles. However, a crosslinking agent, or other means such as UV and heating with or without added peroxides, must be used in order to introduce crosslinking to the hydrophobic component of the block copolymer. Moreover, the biocompatibility or safety of such crosslinked polymer particles has yet to be established.
U.S. Pat. No. 4,745,160 discloses a pharmaceutically or veterinary acceptable amphiphilic, non-cross linked linear, branched or graft block copolymer having polyethylene glycol as the hydrophilic component and poly(D-, L- and DL-lactic acids) as the hydrophobic components. Although the block copolymer is an effective dispersing agent or suspending agent for a hydrophobic drug, the block copolymer has a molecular weight of 5,000 or more and is insoluble in water. Further, the hydrophilic component is at least 50 wt % based on the weight of the block copolymer and the molecular weight of the hydrophobic component is 5,000 or less. In the preparation process, a water-miscible and lyophilizable organic solvent is used. When a mixture of the polymer, drug and organic solvent is mixed with water, precipitates are formed and then the mixture is directly lyophilized to form particles. Therefore, when this particle is dispersed in water, it forms a colloidal suspension containing fine particles wherein hydrophilic components and hydrophobic components are mixed.
U.S. Pat. No. 5,543,158 discloses nanoparticle or microparticle formed of a block copolymer consisting essentially of poly(alkylene glycol) and a biodegradable polymer, poly(lactic acid). In the nanoparticle or microparticle, the biodegradable moieties of the copolymer are in the core of the nanoparticle or microparticle and the poly(alkylene glycol) moieties are on the surface of the nanoparticle or microparticle in an amount effective to decrease uptake of the nanoparticle or microparticle by the reticuloendothelial system. In this patent, the molecular weight of the block copolymer is too high to be soluble in water, and a nanoparticle is prepared by dissolving the block copolymer and a drug in an organic solvent, forming an o/w emulsion by sonication or stirring, and then collecting the precipitated nanoparticles containing the drug. It does not provide the concept of solubilization of hydrophobic drugs. The nanoparticles prepared in this patent are fine particles that are dispersed in water.
EP 0,520,888 A1 discloses a nanoparticle made of a poly(lactic acid) and poly(alkylene oxide) block copolymer. A high molecular weight poly(lactic acid) is used and a surfactant is employed in preparing a colloidal suspension of the nanoparticles. In this patent, nanoparticles are prepared by dissolving the block copolymer and a drug in an organic solvent, emulsifying the organic solution in water, and evaporating the organic solvent to precipitate the nanoparticles containing the drug. The resulting nanoparticles are fine particles having both hydrophilic and hydrophobic components and they are not soluble in water. The above patent does not disclose the concept of solubilization of hydrophobic drugs when the nanoparticles are dispersed in water. Hitherto, there has been no serious effort to solubilize hydrophobic drugs in water by way of using a water soluble micelle, in which the inner core of the micelle can physically trap such drugs.
Accordingly, the present inventors have endeavored to develop an improved water soluble solubilizer which is free of the problems mentioned above, and it has been unexpectedly found that an amphiphilic block copolymer micelle composed of a poly(ethylene oxide) hydrophilic component covering the surface of a hydrophobic core component made of poly(lactic acid), poly(lactic-co-glycolic acid), poly(glycolic acid), poly(.epsilon.-caprolactone) or a mixture thereof, is very effective in solubilizing hydrophobic drugs by physically incorporating them therewithin.
The resulting biodegradable polymeric micelle is water soluble and it is an effective solubilizing agent for a hydrophobic drug. The resulting composition is a solution of the hydrophobic drug carrying micelles and it is suitable for sustained release of the drug in vivo, thereby enhancing the therapeutic effect of the drug. Such effect may be maximized by controlling the molecular weights and the relative ratios of the hydrophilic and hydrophobic blocks.